Increased presynaptic excitability in a migraine with aura mutation.

Migraine is a common and disabling neurological disorder. The headache and sensory amplifications of migraine are attributed to hyperexcitable sensory circuits, but a detailed understanding remains elusive. A mutation in casein kinase 1 delta (CK1δ) was identified in non-hemiplegic familial migraine with aura and advanced sleep phase syndrome. Mice carrying the CK1δT44A mutation were more susceptible to spreading depolarization (the phenomenon that underlies migraine aura), but mechanisms underlying this migraine-relevant phenotype were not known. We used a combination of whole-cell electrophysiology and multiphoton imaging, in vivo and in brain slices, to compare CK1δT44A mice (adult males) to their wild-type littermates. We found that despite comparable synaptic activity at rest, CK1δT44A neurons were more excitable upon repetitive stimulation than wild-type, with a reduction in presynaptic adaptation at excitatory but not inhibitory synapses. The mechanism of this adaptation deficit was a calcium-dependent enhancement of the size of the readily releasable pool of synaptic vesicles, and a resultant increase in glutamate release, in CK1δT44A compared to wild-type synapses. Consistent with this mechanism, CK1δT44A neurons showed an increase in the cumulative amplitude of excitatory post-synaptic currents, and a higher excitation-to-inhibition ratio during sustained activity compared to wild-type. At a local circuit level, action potential bursts elicited in CK1δT44A neurons triggered an increase in recurrent excitation compared to wild-type, and at a network level, CK1δT44A mice showed a longer duration of 'up state' activity, which is dependent on recurrent excitation. Finally, we demonstrated that the spreading depolarization susceptibility of CK1δT44A mice could be returned to wild-type levels with the same intervention (reduced extracellular calcium) that normalized presynaptic adaptation. Taken together, these findings show a stimulus-dependent presynaptic gain of function at glutamatergic synapses in a genetic model of migraine, that accounts for the increased spreading depolarization susceptibility and may also explain the sensory amplifications that are associated with the disease.

Epigenetic underpinnings of the autistic mind: Histone modifications and prefrontal excitation/inhibition imbalance.

Autism spectrum disorder (ASD) is complex neurobehavioral condition influenced by several cellular and molecular mechanisms that are often concerned with synaptogenesis and synaptic activity. Based on the excitation/inhibition (E/I) imbalance theory, ASD could be the result of disruption in excitatory and inhibitory synaptic transmission across the brain. The prefrontal cortex (PFC) is the chief regulator of executive function and can be affected by altered neuronal excitation and inhibition in the course of ASD. The molecular mechanisms involved in E/I imbalance are subject to epigenetic regulation. In ASD, altered enrichment and spreading of histone H3 and H4 modifications such as the activation-linked H3K4me2/3, H3K9ac, and H3K27ac, and repression-linked H3K9me2, H3K27me3, and H4K20me2 in the PFC result in dysregulation of molecules mediating synaptic excitation (ARC, EGR1, mGluR2, mGluR3, GluN2A, and GluN2B) and synaptic inhibition (BSN, EphA7, SLC6A1). Histone modifications are a dynamic component of the epigenetic regulatory elements with a pronounced effect on patterns of gene expression with regards to any biological process. The excitation/inhibition imbalance associated with ASD is based on the excitatory and inhibitory synaptic activity in different regions of the brain, including the PFC, the ultimate outcome of which is highly influenced by transcriptional activity of relevant genes.

Excitation-Inhibition Imbalance in Migraine: From Neurotransmitters to Brain Oscillations.

Migraine is among the most common and debilitating neurological disorders typically affecting people of working age. It is characterised by a unilateral, pulsating headache often associated with severe pain. Despite the intensive research, there is still little understanding of the pathophysiology of migraine. At the electrophysiological level, altered oscillatory parameters have been reported within the alpha and gamma bands. At the molecular level, altered glutamate and GABA concentrations have been reported. However, there has been little cross-talk between these lines of research. Thus, the relationship between oscillatory activity and neurotransmitter concentrations remains to be empirically traced. Importantly, how these indices link back to altered sensory processing has to be clearly established as yet. Accordingly, pharmacologic treatments have been mostly symptom-based, and yet sometimes proving ineffective in resolving pain or related issues. This review provides an integrative theoretical framework of excitation-inhibition imbalance for the understanding of current evidence and to address outstanding questions concerning the pathophysiology of migraine. We propose the use of computational modelling for the rigorous formulation of testable hypotheses on mechanisms of homeostatic imbalance and for the development of mechanism-based pharmacological treatments and neurostimulation interventions.

Enhanced Astrocyte Activity and Excitatory Synaptic Function in the Hippocampus of Pentylenetetrazole Kindling Model of Epilepsy.

Epilepsy is a chronic condition characterized by recurrent spontaneous seizures. The interaction between astrocytes and neurons has been suggested to play a role in the abnormal neuronal activity observed in epilepsy. However, the exact way astrocytes influence neuronal activity in the epileptogenic brain remains unclear. Here, using the PTZ-induced kindling mouse model, we evaluated the interaction between astrocyte and synaptic function by measuring astrocytic Ca2+ activity, neuronal excitability, and the excitatory/inhibitory balance in the hippocampus. Compared to control mice, hippocampal slices from PTZ-kindled mice displayed an increase in glial fibrillary acidic protein (GFAP) levels and an abnormal pattern of intracellular Ca2+-oscillations, characterized by an increased frequency of prolonged spontaneous transients. PTZ-kindled hippocampal slices also showed an increase in the E/I ratio towards excitation, likely resulting from an augmented release probability of excitatory inputs without affecting inhibitory synapses. Notably, the alterations in the release probability seen in PTZ-kindled slices can be recovered by reducing astrocyte hyperactivity with the reversible toxin fluorocitrate. This suggests that astroglial hyper-reactivity enhances excitatory synaptic transmission, thereby impacting the E/I balance in the hippocampus. Altogether, our findings support the notion that abnormal astrocyte-neuron interactions are pivotal mechanisms in epileptogenesis.

Visual illusion susceptibility in autism: A neural model.

While atypical sensory perception is reported among individuals with autism spectrum disorder (ASD), the underlying neural mechanisms of autism that give rise to disruptions in sensory perception remain unclear. We developed a neural model with key physiological, functional and neuroanatomical parameters to investigate mechanisms underlying the range of representations of visual illusions related to orientation perception in typically developed subjects compared to individuals with ASD. Our results showed that two theorized autistic traits, excitation/inhibition imbalance and weakening of top-down modulation, could be potential candidates for reduced susceptibility to some visual illusions. Parametric correlation between cortical suppression, balance of excitation/inhibition, feedback from higher visual areas on one hand and susceptibility to a class of visual illusions related to orientation perception on the other hand provide the opportunity to investigate the contribution and complex interactions of distinct sensory processing mechanisms in ASD. The novel approach used in this study can be used to link behavioural, functional and neuropathological studies; estimate and predict perceptual and cognitive heterogeneity in ASD; and form a basis for the development of novel diagnostics and therapeutics.

GABAergic interneurons in epilepsy: More than a simple change in inhibition.

The pathophysiology of epilepsy has been historically grounded on hyperexcitability attributed to the oversimplified imbalance between excitation (E) and inhibition (I) in the brain. The decreased inhibition is mostly attributed to deficits in gamma-aminobutyric acid-containing (GABAergic) interneurons, the main source of inhibition in the central nervous system. However, the cell diversity, the wide range of spatiotemporal connectivity, and the distinct effects of the neurotransmitter GABA especially during development, must be considered to critically revisit the concept of hyperexcitability caused by decreased inhibition as a key characteristic in the development of epilepsy. Here, we will discuss that behind this known mechanism, there is a heterogeneity of GABAergic interneurons with distinct functions and sources, which have specific roles in controlling the neural network activity within the recruited microcircuit and altered network during the epileptogenic process. This article is part of the Special Issue "NEWroscience 2018.

Astrocyte Activation in the ACC Contributes to Comorbid Anxiety in Chronic Inflammatory Pain and Involves in The Excitation-Inhibition Imbalance.

Neurons within the anterior cingulate cortex (ACC) orchestrate the co-occurrence of chronic pain and anxiety. The ACC hyperactivity plays a crucial role in the emotional impact of neuropathic pain. Astrocyte-mediated neuroinflammatory is responsible for regulating the balance between excitation-inhibition (E/I) in the brain. However, there is limited understanding of the possible contributions of astrocytes in the ACC to comorbidity of anxiety and chronic inflammatory pain. This paper aims to investigate the possible contribution of astrocytes in the ACC to the comorbidity between anxiety and chronic inflammatory pain, as well as their involvement in the E/I imbalance of pyramidal cells. Our results show that CFA rats displayed allodynia and anxiety-like behaviors. The E/I balance in the ACC shifts to excitement in comorbidity of chronic pain and anxiety by western blotting, and electrophysiological recording. Result of RNA-Seq also indicated that E/I imbalance and neuroinflammation of ACC were involved in pain-anxiety comorbidity. Then, positive cells of GFAP but not Iba1 in the contralateral ACC were increased; the mRNA expression of GFAP and its activation-related proinflammatory cytokines (TNF-α, IL-6, and IL-1ß) in the contralateral ACC were also elevated. Furthermore, specific chemogenic inhibition of ACC astrocytes reversed comorbid pain and anxiety and suppressed high ACC excitability. Our data suggest that astrocytes participate in comorbid pain and anxiety and excitation-inhibition imbalance in ACC. Inhibition astrocyte activation can reduce anxiety related to pain and restore the imbalance in the ACC. These findings shed light on the involvement of astrocytes in comorbid conditions, offering valuable insights into a potential therapeutic approach for the co-occurrence of chronic pain and anxiety.

Upconversion-Mediated Optogenetics for the Treatment of Surgery-Induced Postoperative Neurocognitive Dysfunction.

Perioperative neurocognitive disorder (PND) is a common complication in surgical patients. While many interventions to prevent PND have been studied, the availability of treatment methods is limited. Thus, it is crucial to delve into the mechanisms of PND, pinpoint therapeutic targets, and develop effective treatment approaches. In this study, reduced dorsal tenia tecta (DTT) neuronal activity was found to be associated with tibial fracture surgery-induced PND, indicating that a neuronal excitation-inhibition (E-I) imbalance could contribute to PND. Optogenetics in the DTT brain region was conducted using upconversion nanoparticles (UCNPs) with the ability to convert 808 nm near-infrared light to visible wavelengths, which triggered the activation of excitatory neurons with minimal damage in the DTT brain region, thus improving cognitive impairment symptoms in the PND model. Moreover, this noninvasive intervention to modulate E-I imbalance showed a positive influence on mouse behavior in the Morris water maze test, which demonstrates that UCNP-mediated optogenetics is a promising tool for the treatment of neurological imbalance disorders.

Amelioration of olfactory dysfunction in a mouse model of Parkinson's disease via enhancing GABAergic signaling.

BACKGROUND: Olfactory dysfunction is among the earliest non-motor symptoms of Parkinson's disease (PD). As the foremost pathological hallmark, α-synuclein initiates the pathology in the olfactory pathway at the early stage of PD, particularly in the olfactory epithelium (OE) and olfactory bulb (OB). However, the local neural microcircuit mechanisms underlying olfactory dysfunction between OE and OB in early PD remain unknown. RESULTS: We observed that odor detection and discrimination were impaired in 6-month-old SNCA-A53T mice, while their motor ability remained unaffected. It was confirmed that α-synuclein increased and accumulated in OB but not in OE. Notably, the hyperactivity of mitral/tufted cells and the excitation/inhibition imbalance in OB were found in 6-month-old SNCA-A53T mice, which was attributed to the impaired GABAergic transmission and aberrant expression of GABA transporter 1 and vesicular GABA transporter in OB. We further showed that tiagabine, a potent and selective GABA reuptake inhibitor, could reverse the impaired olfactory function and GABAergic signaling in OB of SNCA-A53T mice. CONCLUSIONS: Taken together, our findings demonstrate potential synaptic mechanisms of local neural microcircuit underlying olfactory dysfunction at the early stage of PD. These results highlight the critical role of aberrant GABAergic signaling of OB in early diagnosis and provide a potential therapeutic strategy for early-stage PD.

Ribosome subunits are upregulated in brain samples of a subgroup of individuals with schizophrenia: A systematic gene expression meta-analysis.

One of the new theories accounting for the underlying pathophysiology of schizophrenia is excitation/inhibition imbalance. Interestingly, perturbation in protein synthesis machinery as well as oxidative stress can lead to excitation/inhibition imbalance. We thus performed a systematic meta-analysis of the expression of 79 ribosome subunit genes and two oxidative-stress related genes, HIF1A and NQO1, in brain samples of individuals with schizophrenia vs. healthy controls. We integrated 12 gene expression datasets, following the PRISMA guidelines (overall 511 samples, 253 schizophrenia and 258 controls). Five ribosome subunit genes were significantly upregulated in a subgroup of the patients with schizophrenia, while 24 (30%) showed a tendency for upregulation. HIF1A and NQO1 were also found to be significantly upregulated. Moreover, HIF1A and NQO1 showed positive correlation with the expression of the upregulated ribosome subunit genes. Our results, together with previous findings, suggest a possible role for altered mRNA translation in the pathogenesis of schizophrenia, in association with markers of increased oxidative stress in a subgroup of patients. Further studies should define whether the upregulation of ribosome subunits result in altered mRNA translation, which proteins are modulated and how it characterizes a subgroup of the patients with schizophrenia.

Alteration of Excitation/Inhibition Imbalance in the Hippocampus and Amygdala of Drug-Resistant Epilepsy Patients Treated with Acute Vagus Nerve Stimulation.

An imbalance between excitation (E) and inhibition (I) in the brain has been identified as a key pathophysiology of epilepsy over the years. The hippocampus and amygdala in the limbic system play a crucial role in the initiation and conduction of epileptic seizures and are often referred to as the transfer station and amplifier of seizure activities. Existing animal and imaging studies reveal that the hippocampus and amygdala, which are significant parts of the vagal afferent network, can be modulated in order to generate an antiepileptic effect. Using stereo-electroencephalography (SEEG) data, we examined the E/I imbalance in the hippocampus and amygdala of ten drug-resistant epilepsy children treated with acute vagus nerve stimulation (VNS) by estimating the 1/f power slope of hippocampal and amygdala signals in the range of 1-80 Hz. While the change in the 1/f power slope from VNS-BASE varied between different stimulation amplitudes and brain regions, it was more prominent in the hippocampal region. In the hippocampal region, we found a flatter 1/f power slope during VNS-ON in patients with good responsiveness to VNS under the optimal stimulation amplitude, indicating that the E/I imbalance in the region was improved. There was no obvious change in 1/f power slope for VNS poor responders. For VNS non-responders, the 1/f power slope slightly increased when the stimulation was applied. Overall, this study implies that the regulation of E/I imbalance in the epileptic brain, especially in the hippocampal region, may be an acute intracranial effect of VNS.

Effects of altered excitation-inhibition imbalance by repetitive transcranial magnetic stimulation for self-limited epilepsy with centrotemporal spikes.

Objectives: Patients with self-limited epilepsy with centrotemporal spikes (SeLECTS) with electrical status epilepticus in sleep (ESES) have generalized cognitive impairment, yet treatment options are limited. Our study aimed to examine the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) on SeLECTS with ESES. In addition, we applied electroencephalography (EEG) aperiodic components (offset and slope) to investigate the improvement of rTMS on the excitation-inhibition imbalance (E-I imbalance) in the brain of this group of children. Methods: Eight SeLECTS patients with ESES were included in this study. Low-frequency rTMS (≤1 Hz) was applied for 10 weekdays in each patient. To assess the clinical efficacy and changes in E-I imbalance, EEG recordings were performed both before and after rTMS. Seizure-reduction rate and spike-wave index (SWI) were measured to investigate the clinical effects of rTMS. The aperiodic offset and slope were calculated to explore the effect of rTMS on E-I imbalance. Results: Five of the eight patients (62.5%) were seizure-free within 3 months after stimulation, with treatment effects decreasing with longer follow-ups. The SWI decreased significantly at 3 and 6 months after rTMS compared with the baseline (P = 0.0157 and P = 0.0060, respectively). The offset and slope were compared before rTMS and within 3 months after stimulation. The results showed a significant reduction in the offset after stimulation (P < 0.0001). There was a remarkable increase in slope after the stimulation (P < 0.0001). Conclusion: Patients achieved favorable outcomes in the first 3 months after rTMS. The ameliorative effect of rTMS on SWI may last up to 6 months. Low-frequency rTMS could reduce firing rates in neuronal populations throughout the brain, which was most pronounced at the site of stimulation. A significant reduction in the slope after rTMS treatment suggested an improvement in the E-I imbalance in the SeLECTS.

Reduced sociability in a prenatal immune activation model: Modulation by a chronic blonanserin treatment through the amygdala-hippocampal axis.

The environmental disturbances in a critical neurodevelopmental period exert organizational effects on brain intrinsic plasticity including excitatory and inhibitory (E/I) neurotransmission those can cause the onset of psychiatric illness. We previously reported that treatment of neural precursor cells with N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 induced reduction of GABAergic interneuron differentiation, and these changes recovered by atypical antipsychotic blonanserin treatment in vitro. However, it remains unclear how this treatment affects neural circuit changes in hippocampus and amygdala, which might contribute to the prevention of onset process of schizophrenia. To elucidate the pathogenic/preventive mechanisms underlying prenatal environmental adversity-induced schizophrenia in more detail, we administered poly (I:C) followed by antipsychotics and examined alterations in social/cognitive behaviors, GABA/glutamate-related gene expressions with cell density and E/I ratio, and brain-derived neurotrophic factor (Bdnf) transcript levels, particularly in limbic areas. Treatment with antipsychotic blonanserin ameliorated impaired social/cognitive behaviors and increased parvalbumin (PV)-positive (+) cell density and its mRNA levels as well as Bdnf with long 3'UTR mRNA levels, particularly in the dorsal hippocampus, in rats exposed to maternal immune activation (MIA). Low dose of blonanserin and haloperidol altered GABA and glutamate-related mRNA levels, the E/I ratio, and Bdnf long 3'UTR mRNA levels in the ventral hippocampus and amygdala, but did not attenuate behavioral impairments. These results strongly implicate changes in PV expression, PV(+) GABAergic interneuron density, and Bdnf long 3'UTR expression levels, particularly in the dorsal hippocampus, in the pathophysiology and treatment responses of MIA-induced schizophrenia and highlight the therapeutic potential of blonanserin for developmental stress-related schizophrenia.

Neurobehavioral sex-related differences in Nf1+/- mice: female show a "camouflaging"-type behavior.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous disorder associated with neurodevelopmental disorders including autism spectrum disorder (ASD). This condition has been associated with an increase of gamma-aminobutyric acid (GABA) neurotransmission and, consequently, an excitation/inhibition imbalance associated with autistic-like behavior in both human and animal models. Here, we explored the influence of biological sex in the GABAergic system and behavioral alterations induced by the Nf1+/- mutation in a murine model. METHODS: Juvenile male and female Nf1+/- mice and their wild-type (WT) littermates were used. Hippocampus size was assessed by conventional toluidine blue staining and structural magnetic resonance imaging (MRI). Hippocampal GABA and glutamate levels were determined by magnetic resonance spectroscopy (MRS), which was complemented by western blot for the GABA(A) receptor. Behavioral evaluation of on anxiety, memory, social communication, and repetitive behavior was performed. RESULTS: We found that juvenile female Nf1+/- mice exhibited increased hippocampal GABA levels. Moreover, mutant female displays a more prominent anxious-like behavior together with better memory performance and social behavior. On the other hand, juvenile Nf1+/- male mice showed increased hippocampal volume and thickness, with a decrease in GABA(A) receptor levels. We observed that mutant males had higher tendency for repetitive behavior. CONCLUSIONS: Our results suggested a sexually dimorphic impact of Nf1+/- mutation in hippocampal neurochemistry, and autistic-like behaviors. For the first time, we identified a "camouflaging"-type behavior in females of an animal model of ASD, which masked their autistic traits. Accordingly, like observed in human disorder, in this animal model of ASD, females show larger anxiety levels but better executive functions and production of normative social patterns, together with an imbalance of inhibition/excitation ratio. Contrary, males have more externalizing disorders, such as hyperactivity and repetitive behaviors, with memory deficits. The ability of females to camouflage their autistic traits creates a phenotypic evaluation challenge that mimics the diagnosis difficulty observed in humans. Thus, we propose the study of the Nf1+/- mouse model to better understand the sexual dimorphisms of ASD phenotypes and to create better diagnostic tools.

Hippocampal SIRT1-Mediated Synaptic Plasticity and Glutamatergic Neuronal Excitability Are Involved in Prolonged Cognitive Dysfunction of Neonatal Rats Exposed to Propofol.

Neonates who receive repeated or prolonged general anesthesia before the age of 4 are at a significantly higher risk of developing cognitive dysfunction later in life. In this study, we investigated the effects of repeated neonatal propofol exposure on hippocampal synaptic plasticity, neuronal excitability, and cognitive function. Adeno-associated SIRT1 virus with CaMKIIɑ promotor and a viral vector carrying the photosensitive gene ChR2 with the CaMKIIɑ promotor, as well as their control vectors, were stereotaxically injected into the hippocampal CA1 region of postnatal day 5 (PND-5) rats. PND-7 rats were given intraperitoneal injection of 60 mg/kg propofol or fat emulsion for three consecutive days. Western blotting, Golgi staining, and double immunofluorescence staining were used to evaluate the SIRT1 expression, synaptic plasticity, and the excitability of neurons in the hippocampal CA1 region. The Morris water maze (MWM) test was conducted on PND-30 to assess the learning and memory abilities of rats. Repeated neonatal propofol exposure reduced SIRT1 expression, suppressed synaptic plasticity, decreased glutamatergic neuron excitability in the hippocampus, and damaged learning and memory abilities. Overexpression of SIRT1 attenuated propofol-induced cognitive dysfunction, excitation-inhibition imbalance, and synaptic plasticity damage. After optogenetic stimulation of glutamatergic neurons in the hippocampal CA1 region, the learning and memory abilities of rats exposed to propofol were improved on PND-30. Our findings demonstrate that SIRT1 plays an important role in cognitive dysfunction induced by repeated neonatal propofol exposure by suppressing synaptic plasticity and neuronal excitability.

Increased amplitude of hippocampal low frequency fluctuations in early psychosis: A two-year follow-up study.

Neuroimaging studies have revealed hippocampal hyperactivity in schizophrenia. In the early stage of the illness, hyperactivity is present in the anterior hippocampus and is thought to spread to other regions as the illness progresses. However, there is limited evidence for changes in basal hippocampal function following the onset of psychosis. Resting state functional MRI signal amplitude may be a proxy measure for increased metabolism and disrupted oscillatory activity, both consequences of an excitation/inhibition imbalance underlying hippocampal hyperactivity. Here, we used fractional amplitude of low frequency fluctuations (fALFF) to test the hypothesis of progressive hippocampal hyperactivity in a two-year longitudinal case-control study. We found higher fALFF in the anterior and posterior hippocampus of individuals in the early stage of non-affective psychosis at study entry. Contrary to our hypothesis of progressive hippocampal dysfunction, we found evidence for normalization of fALFF over time in psychosis. Our findings support a model in which hippocampal fALFF is a marker of psychosis vulnerability or acute illness state rather than an enduring feature of the illness.

Development of Mechanistic Neural Mass (mNM) Models that Link Physiology to Mean-Field Dynamics.

Brain rhythms emerge from the mean-field activity of networks of neurons. There have been many efforts to build mathematical and computational embodiments in the form of discrete cell-group activities-termed neural masses-to understand in particular the origins of evoked potentials, intrinsic patterns of activities such as theta, regulation of sleep, Parkinson's disease related dynamics, and mimic seizure dynamics. As originally utilized, standard neural masses convert input through a sigmoidal function to a firing rate, and firing rate through a synaptic alpha function to other masses. Here we define a process to build mechanistic neural masses (mNMs) as mean-field models of microscopic membrane-type (Hodgkin Huxley type) models of different neuron types that duplicate the stability, firing rate, and associated bifurcations as function of relevant slow variables - such as extracellular potassium - and synaptic current; and whose output is both firing rate and impact on the slow variables - such as transmembrane potassium flux. Small networks composed of just excitatory and inhibitory mNMs demonstrate expected dynamical states including firing, runaway excitation and depolarization block, and these transitions change in biologically observed ways with changes in extracellular potassium and excitatory-inhibitory balance.

Behavioral Deficits in Adolescent Mice after Sub-Chronic Administration of NMDA during Early Stage of Postnatal Development.

Neurodevelopmental disorders are complex conditions that pose difficulty in the modulation of proper motor, sensory and cognitive function due to dysregulated neuronal development. Previous studies have reported that an imbalance in the excitation/ inhibition (E/I) in the brain regulated by glutamatergic and/or GABAergic neurotransmission can cause neurodevelopmental and neuropsychiatric behavioral deficits such as autism spectrum disorder (ASD). NMDA acts as an agonist at the NMDA receptor and imitates the action of the glutamate on that receptor. NMDA however, unlike glutamate, only binds to and regulates the NMDA receptor subtypes and not the other glutamate receptors. This study seeks to determine whether NMDA administration in mice i.e., over-activation of the NMDA system would result in long-lasting behavioral deficits in the adolescent mice. Both gender mice were treated with NMDA or saline at early postnatal developmental period with significant synaptogenesis and synaptic maturation. On postnatal day 28, various behavioral experiments were conducted to assess and identify behavioral characteristics. NMDA-treated mice show social deficits, and repetitive behavior in both gender mice at adolescent periods. However, only the male mice but not female mice showed increased locomotor activity. This study implies that neonatal exposure to NMDA may illicit behavioral features similar to ASD. This study also confirms the validity of the E/I imbalance theory of ASD and that NMDA injection can be used as a pharmacologic model for ASD. Future studies may explore the mechanism behind the gender difference in locomotor activity as well as the human relevance and therapeutic significance of the present findings.

Right Anterior Theta Hypersynchrony as a Quantitative Measure Associated with Autistic Traits and K-Cl Cotransporter KCC2 Polymorphism.

Our aim was to use theta coherence as a quantitative trait to investigate the relation of the polymorphisms in NKCC1 (rs3087889) and KCC2 (rs9074) channel protein genes to autistic traits (AQ) in neurotypicals. Coherence values for candidate connection regions were calculated from eyes-closed resting EEGs in two independent groups. Hypersynchrony within the right anterior region was related to AQ in both groups (p < 0.05), and variability in this hypersynchrony was related to the rs9074 polymorphism in the total group (p < 0.05). In conclusion, theta hypersynchrony within the right anterior region during eyes-closed rest can be considered a quantitative measure for autistic traits. Replicating our findings in two independent populations with different backgrounds strengthens the validity of the current study.

Neural Hyperactivity Is a Core Pathophysiological Change Induced by Deletion of a High Autism Risk Gene Ash1L in the Mouse Brain.

ASH1L is one of the highest risk genes associated with autism spectrum disorder (ASD) and intellectual disability (ID). Our recent studies demonstrate that loss of Ash1l in the mouse brain is sufficient to induce ASD/ID-like behavioral and cognitive deficits, suggesting that disruptive ASH1L mutations are likely to have a positive correlation with ASD/ID genesis. However, the core pathophysiological changes in the Ash1l-deficient brain remain largely unknown. Here we show that loss of Ash1l in the mouse brain causes locomotor hyperactivity, high metabolic activity, and hyperactivity-related disturbed sleep and lipid metabolic changes. In addition, the mutant mice display lower thresholds for the convulsant reagent-induced epilepsy and increased neuronal activities in multiple brain regions. Thus, our current study reveals that neural hyperactivity is a core pathophysiological change in the Ash1l-deficient mouse brain, which may function as a brain-level mechanism leading to the Ash1l-deletion-induced brain functional abnormalities and autistic-like behavioral deficits.